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Empagliflozin improves high-sensitive cardiac troponin-I and high-density lipoprotein cholesterol in patients with type 2 diabetes mellitus and coronary artery disease: a post-hoc analysis of EMPA-CARD Trial

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Abstract

Background

Empagliflozin is a sodium glucose cotransporter-2 (SGLT2) inhibitor that has been suggested to improve cardiac function and vascular recovery. The risk of coronary artery diseases is much higher in diabetic patients and is associated with greater morbidity and mortality. High-sensitivity cardiac troponin-I (hs-cTnI) is an important prognostic biomarker in cardiac diseases. Therefore, this study aimed to investigate the effect of empagliflozin compared to placebo on changes in hs-cTnI and lipid profile after 26 weeks of treatment.

Methods

This was an ancillary study in a randomized trial of patients with concomitant type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) (The EMPA-CARD study). Patients who were already on standard anti-diabetic/anti-ischemic medications were randomized to receive either placebo or empagliflozin 10 mg/daily. Serum hs-cTnI and lipid profile were measured at baseline and after 26 weeks.

Results

Of the 95 randomized patients, hs-cTnI and lipid profile were measured for a total of 77 patients. No significant difference was observed regarding the baseline characteristics between the two arms. Compared to placebo, empagliflozin significantly reduced hs-cTnI after 26 weeks (mean difference (MD) of -13.242, 95%CI: -14.151 to -12.333, p < 0.001). In the empagliflozin group, non-significant reductions in total cholesterol, LDL-C, and triglyceride have resulted; however, there was an increase in HDL-C level (MD = 2.40,95%CI:0.16–4.60, p < 0.04).

Conclusion

Empagliflozin compared to placebo was superior in reducing circulating hs-cTnI that may indicate improvements in cardiomyocytes function in patients with T2DM and CAD. Moreover, empagliflozin had a modest impact on the serum lipid profile biomarkers.

Trial registration

The original EMPA-CARD study has been registered in Iranian Registry of Clinical Trials. www.IRCT.ir, Identifier: IRCT20190412043247N2. Registration Date: 6/13/2020. Registration timing: prospective.

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Data availability

The data/information supporting this study is available from the corresponding author upon reasonable request.

Abbreviations

T2DM :

Type 2 diabetes mellitus

CAD :

Coronary artery disease

Hs-cTnI :

High-sensitivity cardiac troponin-I

MI :

Myocardial infarction

SGLT2 inhibitors :

Sodium-glucose cotransporter-2 inhibitors

LDL-C :

Low-density lipoproteins cholesterol

RCT :

Randomized controlled trial

BMI :

Body mass index

ACS :

Acute coronary syndrome

CABG surgery :

Coronary artery bypass graft surgery

TIA :

Transient ischemic attack

CVA :

Cerebrovascular accident

HDL-C :

High-density lipoprotein cholesterol

TG :

Triglyceride

References

  1. Lazar DR, Lazar F-L, Homorodean C, Cainap C, Focsan M, Cainap S, et al. High-sensitivity troponin: a review on characteristics, assessment, and clinical implications. Dis Markers. 2022;2022.

  2. Hillis GS, Welsh P, Chalmers J, Perkovic V, Chow CK, Li Q, et al. The relative and combined ability of high-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide to predict cardiovascular events and death in patients with type 2 diabetes. Diabetes Care. 2014;37(1):295–303.

    Article  CAS  PubMed  Google Scholar 

  3. Chilton R, Tikkanen I, Cannon C, Crowe S, Woerle H, Broedl U, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17(12):1180–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sinha B, Ghosal S. Meta-analyses of the effects of DPP-4 inhibitors, SGLT2 inhibitors and GLP1 receptor analogues on cardiovascular death, myocardial infarction, stroke and hospitalization for heart failure. Diabetes Res Clin Pract. 2019;150:8–16.

    Article  CAS  PubMed  Google Scholar 

  5. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.

    Article  CAS  PubMed  Google Scholar 

  6. Calapkulu M, Cander S, Gul OO, Ersoy C. Lipid profile in type 2 diabetic patients with new dapagliflozin treatment; actual clinical experience data of six months retrospective lipid profile from single center. Diabetes Metab Syndr. 2019;13(2):1031–4.

    Article  PubMed  Google Scholar 

  7. Sanchez-Garcia A, Simental-Mendia M, Millan-Alanis JM, Simental-Mendia LE. Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: a systematic review and meta-analysis of 48 randomized controlled trials. Pharmacol Res. 2020;160: 105068.

    Article  CAS  PubMed  Google Scholar 

  8. Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2014;5(2):355–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gohari S, Reshadmanesh T, Khodabandehloo H, Fathi M, Ahangar H, Arsang-Jang S, et al. Study rationale and design of a study of EMPAgliflozin’s effects in patients with type 2 diabetes mellitus and Coronary ARtery disease: the EMPA-CARD randomized controlled trial. BMC Cardiovasc Disord. 2021;21(1):1–11.

    Article  Google Scholar 

  10. Vickers AJ. Parametric versus non-parametric statistics in the analysis of randomized trials with non-normally distributed data. BMC Med Res Methodol. 2005;5(1):1–12.

    Article  Google Scholar 

  11. Tsutamoto T, Kawahara C, Nishiyama K, Yamaji M, Fujii M, Yamamoto T, et al. Prognostic role of highly sensitive cardiac troponin I in patients with systolic heart failure. Am Heart J. 2010;159(1):63–7.

    Article  CAS  PubMed  Google Scholar 

  12. Bohula May EA, Bonaca MP, Jarolim P, Antman EM, Braunwald E, Giugliano RP, et al. Prognostic performance of a high-sensitivity cardiac troponin I assay in patients with non–ST-elevation acute coronary syndrome. Clin Chem. 2014;60(1):158–64.

    Article  PubMed  Google Scholar 

  13. Januzzi JL Jr, Butler J, Jarolim P, Sattar N, Vijapurkar U, Desai M, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol. 2017;70(6):704–12.

    Article  CAS  PubMed  Google Scholar 

  14. Paolisso P, Bergamaschi L, Santulli G, Gallinoro E, Cesaro A, Gragnano F, et al. Infarct size, inflammatory burden, and admission hyperglycemia in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: a multicenter international registry. Cardiovasc Diabetol. 2022;21(1):77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Packer M, Januzzi JL, Ferreira JP, Anker SD, Butler J, Filippatos G, et al. Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial. Eur J Heart Fail. 2021;23(9):1529–38.

    Article  CAS  PubMed  Google Scholar 

  16. Jensen J, Omar M, Kistorp C, Tuxen C, Poulsen MK, Faber J, et al. Effect of empagliflozin on multiple biomarkers in heart failure: insights from the empire heart failure trial. Circ Heart Fail. 2022. https://doi.org/10.1161/CIRCHEARTFAILURE.121.009333.

  17. Lee MM, Brooksbank KJ, Wetherall K, Mangion K, Roditi G, Campbell RT, et al. Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation. 2021;143(6):516–25.

    Article  CAS  PubMed  Google Scholar 

  18. Januzzi JL Jr, Butler J, Zannad F, Filippatos G, Ferreira JP, Pocock SJ, et al. Prognostic implications of N-Terminal Pro-B-Type natriuretic peptide and high-sensitivity cardiac troponin T in EMPEROR-preserved. JACC Heart Fail. 2022;10(7):512–24.

    Article  PubMed  Google Scholar 

  19. Zelniker TA, Morrow DA, Mosenzon O, Goodrich EL, Jarolim P, Murphy SA, et al. Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium-glucose co-transporter 2 inhibitor therapy in DECLARE-TIMI 58. Eur J Heart Fail. 2021;23(6):1026–36.

    Article  CAS  PubMed  Google Scholar 

  20. Verma S, McMurray JJ. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108–17.

    Article  CAS  PubMed  Google Scholar 

  21. Kocak EF, Kocak C, Aksoy A, Isiklar OO, Akcilar R, Ozdomanic IF, et al. High-sensitivity cardiac troponin T is more helpful in detecting peri-operative myocardial injury and apoptosis during coronary artery bypass graft surgery: cardiovascular topics. Cardiovasc J Afr. 2015;26(6):234–41.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fadini GP, Bonora BM, Zatti G, Vitturi N, Iori E, Marescotti MC, et al. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovasc Diabetol. 2017;16(1):1–10.

    Article  Google Scholar 

  23. Pujante P, Ares J, Maciá C, Escobedo RR, Menéndez E, Delgado E. Efficacy of sodium glucose cotransporter 2 inhibitors as an adjunct treatment for patients with diabetes type 2. Med Clín (English Edition). 2019;152(11):438–41.

    Article  Google Scholar 

  24. Ozcelik S, Celik M, Vural A, Aydin B. The effect of low and high dose empagliflozin on HbA1c and lipid profile in type 2 diabetes mellitus: a real-world data. North Clin İstanbul. 2020;7(2):167.

    Google Scholar 

  25. Castellana M, Cignarelli A, Brescia F, Perrini S, Natalicchio A, Laviola L, et al. Efficacy and safety of GLP-1 receptor agonists as add-on to SGLT2 inhibitors in type 2 diabetes mellitus: a meta-analysis. Sci Rep. 2019;9(1):1–8.

    Article  Google Scholar 

  26. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34(7):1707–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lund SS, Sattar N, Salsali A, Neubacher D, Ginsberg HN. Potential contribution of haemoconcentration to changes in lipid variables with empagliflozin in patients with type 2 diabetes: a post hoc analysis of pooled data from four phase 3 randomized clinical trials. Diabetes Obes Metab. 2021;23(12):2763–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Rau M, Thiele K, Hartmann N-UK, Möllmann J, Wied S, Böhm M, et al. Effects of empagliflozin on lipoprotein subfractions in patients with type 2 diabetes: data from a randomized, placebo-controlled study. Atherosclerosis. 2021;330:8–13.

  29. Briand F, Mayoux E, Brousseau E, Burr N, Urbain I, Costard C, et al. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism. Diabetes. 2016;65(7):2032–8.

    Article  CAS  PubMed  Google Scholar 

  30. Szekeres Z, Toth K, Szabados E. The effects of SGLT2 inhibitors on lipid metabolism. Metabolites. 2021;11(2):87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kovacs C, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle H, et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab. 2014;16(2):147–58.

    Article  CAS  PubMed  Google Scholar 

  32. Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S, Group S. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care. 2015;38(3):365-72.

  33. Osataphan S, Macchi C, Singhal G, Chimene-Weiss J, Sales V, Kozuka C, et al. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and-independent mechanisms. JCI insight. 2019;4(5).

  34. Adingupu DD, Göpel SO, Grönros J, Behrendt M, Sotak M, Miliotis T, et al. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob−/− mice. Cardiovasc Diabetol. 2019;18(1):1–15.

    Article  Google Scholar 

  35. Li D, Wu T, Wang T, Wei H, Wang A, Tang H, et al. Effects of sodium glucose cotransporter 2 inhibitors on risk of dyslipidemia among patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Pharmacoepidemiol Drug Saf. 2020;29(5):582–90.

    Article  CAS  PubMed  Google Scholar 

  36. Basu D, Huggins L-A, Scerbo D, Obunike J, Mullick AE, Rothenberg PL, et al. Mechanism of increased LDL (low-density lipoprotein) and decreased triglycerides with SGLT2 (sodium-glucose cotransporter 2) inhibition. Arterioscler Thromb Vasc Biol. 2018;38(9):2207–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lee MH, Neeland IJ, de Albuquerque RN, Hughes C, Malloy CR, Jin ES. A randomized clinical trial evaluating the effect of empagliflozin on triglycerides in obese adults: role of visceral fat. Metabolism open. 2022;13: 100161.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all the patients and collaborators for their patience and cooperation through the study.

Funding

The Original EMPA-CARD study was funded by Dr. Abidi Pharmaceutical Company® and Zanjan University of Medical Sciences (Grant Number: 1602001000).

Author information

Authors and Affiliations

  1. Department of Cardiology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Homa Taheri, Samin Ghanbari, Mohsen Dadashi, Atieh Asgari & Hassan Ahangar

  2. Endocrinology and Metabolism Research Centre, Vali-E-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Hossein Chiti

  3. Student Research Center, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Tara Reshadmanesh & Sepehr Gohari

  4. Department of Pathology, Mousavi Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Ahmad Jalilvand

  5. Department of Biostatistics, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Shahram Arsang-Jang

  6. Department of Medicine, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

    Faramarz Ismail-Beigi

  7. Endocrine Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahsa Mahjani

  8. Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran

    Amir Karbalaee‑Hasani

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  1. Homa Taheri
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Contributions

All authors have participated in the work and have reviewed and agree with the content of the article. HT: Conceptualization, main investigator, Outcome assessor. HC: Supervision, critical revision, patient follow up. TR and SEP G: Study design, conceptualization, outcome assessor. AJ: Study design, resource. SAJ: Statistical Analysis, data curation. FIB: Supervision, study design. SAM G, MD and AA: patient follow up. MM: Manuscript draft. AKH: Outcome assessor. HA: Project Administration, supervision, resource, manuscript editing, patient follow up.

Corresponding author

Correspondence to Hassan Ahangar.

Ethics declarations

Ethics approval and consent to participate

All methods were conducted in accordance with relevant guidelines and regulations. This study was approved by the ethics committee of Zanjan university of Medical Sciences (ID: IR.ZUMS.REC.A-12–594-29). Moreover, the study protocol of the original study was prospectively registered on the Iranian Registry of Clinical Trials (www.IRCT.ir, Identifier: IRCT20190412043247N2). All patients were provided with written informed consent prior to the recruitment.

Consent for publication

Not applicable.

Role of Dr. Abidi Pharmaceutical Company

The company supplied the medication and placebo for the original study. The company had no role in the development of the protocol, process of the study, or preparation of this manuscript.

Competing interest

The authors contributing to the study have nothing relevant to disclose.

Conflict of interest

None Declared.

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Taheri, H., Chiti, H., Reshadmanesh, T. et al. Empagliflozin improves high-sensitive cardiac troponin-I and high-density lipoprotein cholesterol in patients with type 2 diabetes mellitus and coronary artery disease: a post-hoc analysis of EMPA-CARD Trial. J Diabetes Metab Disord 22, 1723–1730 (2023). https://doi.org/10.1007/s40200-023-01305-2

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